Zometa News

ADVERSE REACTIONS

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypercalcemia of Malignancy

The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.

Renal Toxicity

Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [ see Warnings And Precautions (5) and Dosage And Administration (2) ].

Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.

Table 3: Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System

Zometa

Pamidronate

4 mg

90 mg

n (%)

n (%)

Patients Studied

Total No. of Patients Studied

86

(100)

103

(100)

Total No. of Patients with any AE

81

(94)

95

(92)

Body as a Whole

Fever

38

(44)

34

(33)

Progression of Cancer

14

(16)

21

(20)

Cardiovascular

Hypotension

9

(11)

2

(2)

Digestive

Nausea

25

(29)

28

(27)

Constipation

23

(27)

13

(13)

Diarrhea

15

(17)

17

(17)

Abdominal Pain

14

(16)

13

(13)

Vomiting

12

(14)

17

(17)

Anorexia

8

(9)

14

(14)

Hemic and Lymphatic System

Anemia

19

(22)

18

(18)

Infections

Moniliasis

10

(12)

4

(4)

Laboratory Abnormalities

Hypophosphatemia

11

(13)

2

(2)

Hypokalemia

10

(12)

16

(16)

Hypomagnesemia

9

(11)

5

(5)

Musculoskeletal

Skeletal Pain

10

(12)

10

(10)

Nervous

Insomnia

13

(15)

10

(10)

Anxiety

12

(14)

8

(8)

Confusion

11

(13)

13

(13)

Agitation

11

(13)

8

(8)

Respiratory

Dyspnea

19

(22)

20

(19)

Coughing

10

(12)

12

(12)

Urogenital

Urinary Tract Infection

12

(14)

15

(15)

The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence.

Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa.

Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Ocular Adverse Events

Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use. No cases of iritis, scleritis or uveitis were reported during these clinical trials.

Multiple Myeloma and Bone Metastases of Solid Tumors

The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.

Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug.

Table 6: Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

Zometa

Pamidronate

Placebo

4 mg

90 mg

n (%)

n (%)

n (%)

Patients Studied

Total No. of Patients

1031

(100)

556

(100)

455

(100)

Total No. of Patients with any AE

1015

(98)

548

(99)

445

(98)

Blood and Lymphatic

Anemia

344

(33)

175

(32)

128

(28)

Neutropenia

124

(12)

83

(15)

35

(8)

Thrombocytopenia

102

(10)

53

(10)

20

(4)

Gastrointestinal

Nausea

476

(46)

266

(48)

171

(38)

Vomiting

333

(32)

183

(33)

122

(27)

Constipation

320

(31)

162

(29)

174

(38)

Diarrhea

249

(24)

162

(29)

83

(18)

Abdominal Pain

143

(14)

81

(15)

48

(11)

Dyspepsia

105

(10)

74

(13)

31

(7)

Stomatitis

86

(8)

65

(12)

14

(3)

Sore Throat

82

(8)

61

(11)

17

(4)

General Disorders and Administration Site

Fatigue

398

(39)

240

(43)

130

(29)

Pyrexia

328

(32)

172

(31)

89

(20)

Weakness

252

(24)

108

(19)

114

(25)

Edema Lower Limb

215

(21)

126

(23)

84

(19)

Rigors

112

(11)

62

(11)

28

(6)

Infections

Urinary Tract Infection

124

(12)

50

(9)

41

(9)

Upper Respiratory Tract Infection

101

(10)

82

(15)

30

(7)

Metabolism

Anorexia

231

(22)

81

(15)

105

(23)

Weight Decreased

164

(16)

50

(9)

61

(13)

Dehydration

145

(14)

60

(11)

59

(13)

Appetite Decreased

130

(13)

48

(9)

45

(10)

Musculoskeletal

Bone Pain

569

(55)

316

(57)

284

(62)

Myalgia

239

(23)

143

(26)

74

(16)

Arthralgia

216

(21)

131

(24)

73

(16)

Back Pain

156

(15)

106

(19)

40

(9)

Pain in Limb

143

(14)

84

(15)

52

(11)

Neoplasms

Malignant Neoplasm Aggravated

205

(20)

97

(17)

89

(20)

Nervous

Headache

191

(19)

149

(27)

50

(11)

Dizziness (excluding vertigo)

180

(18)

91

(16)

58

(13)

Insomnia

166

(16)

111

(20)

73

(16)

Paresthesia

149

(15)

85

(15)

35

(8)

Hypoesthesia

127

(12)

65

(12)

43

(10)

Psychiatric

Depression

146

(14)

95

(17)

49

(11)

Anxiety

112

(11)

73

(13)

37

(8)

Confusion

74

(7)

39

(7)

47

(10)

Respiratory

Dyspnea

282

(27)

155

(28)

107

(24)

Cough

224

(22)

129

(23)

65

(14)

Skin

Alopecia

125

(12)

80

(14)

36

(8)

Dermatitis

114

(11)

74

(13)

38

(8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8.

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group.

Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.

Renal Toxicity

In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9).

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes.

The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate.

In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose.

6.2 Postmarketing Experience

The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Osteonecrosis of the Jaw

Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [ see Warnings And Precautions (5) ].

Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [ see Warnings And Precautions (5)].

Ocular Adverse Events

Cases of uveitis and episcleritis have been reported during postmarketing use. Bisphosphonates may be associated with ocular inflammation such as uveitis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued.

Hypersensitivity Reactions

There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported.